Systematic review: interferon-free regimens for patients with
HCV-related Child C cirrhosis
M. Guarino*, F. Morisco*, M. R. Valvano†, A. M. Ippolito† , M. Librandi‡, N. Andriulli§, M. Greco¶, A. Amoruso**, A. Iacobellis†, G. Niro†, N. Caporaso* & A. Andriulli†
*Gastroenterology Unit, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy. †Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy. ‡Pharmacia Librandi, Ciro Marina, Italy.
§Pharmacia Tor Millina, Rome, Italy. ¶Division of Internal Medicine and Clinical Immunology, San Martino Hospital, IRCCS, Genova, Italy. **Division of Emergency Medicine, San Carlo Hospital, Potenza, Italy.
Correspondence to: Dr A. Andriulli, Division of Gastroenterology,“Casa Sollievo Sofferenza” Hospital, IRCCS, Viale Cappuccini 1, 71013 San Giovanni Rotondo, Italy
email: a.andriulli@operapadrepio.it
Publication data
Submitted 1 December 2016 First decision 21 January 2017 Resubmitted 21 January 2017 Resubmitted 7 February 2017 Accepted 7 February 2017 EV Pub Online 6 March 2017 The Handling Editor for this article was Professor Geoffrey Dusheiko, and this uncommissioned review was accepted for publication after full peer-review.
SUMMARY Background
It is unclear whether the efficacy and long-term outcome of treating patients with hepatitis C virus (HCV)-positive cirrhosis with the new pro-tease inhibitors will extend to those with Child C cirrhosis.
Aim
To assess the effectiveness of the interferon-free regimens in Child C cir-rhotic patients with HCV infection.
Methods
A systematic Medline search was conducted to retrieve studies describing the treatment of Child C patients with direct-acting agents. Citations from identified studies were cross-referenced and abstracts from European Asso-ciation for the Study of the Liver (EASL) and American AssoAsso-ciation for the Study of Liver Disease (AASLD) meetings were checked. Extracted data were evaluated using a meta-analysis to calculate a weighted response rate. Results
Seven full-text records and two conference abstracts were retained for analysis from the 649 records identified. Data from an Italian real-life trial were also interrogated. Information on treatment outcome was available for 228 of the 240 Child C patients evaluated in the 10 trials. Overall, the weighted mean sus-tained virological response (SVR12) was 74.9% (95% CI: 65.6–82.4%). Neither duration of treatment (24 or 12 weeks), nor addition of ribavirin influenced these rates. The weighted SVR12 was 65.4% (95% CI: 46.8–80.2) after sofosbu-vir/simeprevir, 76.0% (95% CI: 54.4–89.3%) after sofosbuvir/daclatasvir and 83.0% (95% CI: 73.4–89.6) after sofosbuvir/ledipasvir. Some studies did not provide information on the rate of post-treatment relapse or functional improvement. However, in those studies that did provide such data, a relapse was documented in 12.1% of patients and an improvement of≥2 points on the model for end-stage liver disease (MELD) score in 61.1% of patients.
Conclusion
The improvement in MELD scores strongly suggests HCV-positive patients with Child C cirrhosis should be treated with these agents.
INTRODUCTION
Cirrhosis encompasses a spectrum of clinical entities ranging from early (compensated) to more severe (de-compensated) cirrhosis and terminal end-stage liver dis-ease. Compensated cirrhosis is also heterogeneous with more severe forms observed when oesophageal varices, a reflection of portal hypertension, become evident.1
Patients with hepatitis C virus(HCV)-related cirrhosis are at risk of developing life-threatening complications, such as decompensated liver disease and hepatocellular carcinoma (HCC), or may face an orthotopic liver trans-plant or death in cases with unmanageable, terminal dis-ease.2, 3 Antiviral treatment has the potential to improve long-term outcomes for patients with cirrhosis, and viral clearance is associated with histological improvement, a decreased risk of HCC, and a reduced incidence of decompensation and of liver- and non liver-related mor-tality.4, 5
A sustained virological response with a positive impact on outcome in patients with HCV-related cir-rhosis has been documented following therapy with peg-interferon and ribavirin.6, 7 Initial and fragmentary information concerning a similar favourable effect fol-lowing treatment with the new direct acting antivirals has been also reported.8–10 However, previous data have been derived from the evaluation of patients with early cirrhosis, that is those in classes A and B of the Child classification. It remains unclear whether the therapeutic benefits will extend to patients treated for more advanced disease (Child C patients). Child C patients have been traditionally denied therapy with peg-inter-feron and ribavirin due to concerns about the safety of these regimens in patients with extreme derangements of liver function. A similar attitude is evident in studies evaluating the benefits of therapy with the new anti-viral drugs, with Child C patients under-represented both in registrative clinical trials and real-worlds set-tings, although in most need of viral eradication. The low number of Child C patients treated so far with the new antivirals in the studies has precluded a definitive conclusion about the benefits and harms of treating this particular subgroup of patients.
In order to highlight the value of therapy for patients with Child C cirrhosis in most need of a reduction in the liver impairment caused by HCV infection, this sys-tematic review seeks to assess the effectiveness of the interferon-free regimens in clinical practice in these patients, quantitatively synthesise available evidence where possible and estimate a weighed response follow-ing treatment with the new products.
METHODS
Literature search and selection of primary studies The strategy for building the evidence base for the treatment of patients with cirrhosis and HCV infection consisted of two steps. First, an electronic, systematic review of the avail-able evidence in the literature, conducted in accordance with the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions11 was undertaken to identify all studies. Second, proceedings of the 2015 and 2016 Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), and of the 2016 Annual Conference of the European Association for the Study of the Liver (EASL) were hand searched. The systematic litera-ture review was performed via a Medline search using the following index terms: cirrhosis AND HCV infection AND sofosbuvir (260 items identified), OR simeprevir (125 records retrieved), OR daclatasvir (101 articles), OR ledi-pasvir (93 items), OR ombitasvir/paritaprevir and dasabuvir (52 records). The final search was conducted on October 2016. Eighteen relevant abstracts were retrieved by reading the proceeding of the three scientific conferences.
Figure 1 presents the PRISMA flow diagram for the selection of studies. A total of 649 studies were identi-fied. Studies were excluded if they were in languages other than English, did not separately report outcome data for patients with Child A, B or C cirrhosis, or referred to transplanted patients. Duplicate publications, narrative reviews and editorials were also excluded.
Data extraction and management
All information was extracted using a standardised data abstraction form. Data retrieved included: study character-istics (whether clinical trials or interventional studies); main infecting HCV genotypes; treatment history (na€ıve or treat-ment experienced); schedules of the direct acting antiviral agents administered, including dose and duration; concomi-tant use of ribavirin; efficacy of therapy as ascertained by a sustained virological response at 12 weeks following treat-ment (SVR12); change in the model for end-stage liver dis-ease (MELD) score at 12 weeks after treatment; and safety outcomes for the longest reported treatment and follow-up period. Only data specifically referring to Child C patients were extracted from the included studies by a single author and checked by a second independent reviewer. Any dis-agreements were resolved through discussion.
Data synthesis
The primary efficacy outcome was SVR12 (undetectable HCV-RNA levels 12 weeks after the end of therapy).
Owing to the risk of overestimating a beneficial outcome in trials not designed specifically for patients with Child C cirrhosis undergoing antiviral therapy and including very few patients with Child C cirrhosis, separate analy-ses were performed for each treatment schedules, dose and duration, and for the concomitant use or not of rib-avirin, whenever possible.
Statistical analyses
SVR12 rates were the measure of interest in this meta-analysis. Given the small number of patients and the very low or very high numbers in some studies, the 95% confidence intervals were calculated using the Wilson score interval.12 Subgroup analyses were carried out to explore the impact on the SVR rate of treat-ment duration (24 or 12 weeks), the inclusion of rib-avirin in the treatment schedule and the different new drugs regimens. We used random rather than fixed-effects models to estimate pooled proportions in order to account for the heterogeneity.13 All analyses were performed using the Comprehensive
Meta-analysis software (Version 2.2061, Biostat, Engle-wood, NJ, USA).
RESULTS
Figure 1 shows the PRISMA flow diagram of the litera-ture selection process. Seven full-text records14–20 and two conference abstracts21, 22 were retained for analysis. Additional information for one selected trial19 was retrieved from a follow-up study of the same cohort of patients.23 Of the nine selected studies, three were clini-cal trials,14, 15, 18 and five were real-life studies with a prospective19, 20 or a retrospective design;16, 17, 21 the design of the ninth investigation was not explained.22 Data from an ongoing large, prospective Italian program evaluating treatment with the new antivirals in patients with chronic HCV infection were also interrogated,24 and information for patients with Child C cirrhosis was extracted and pooled in the final analysis. The main characteristics of patients with cirrhosis evaluated in the 10 selected studies are shown in Table 1. The number of patients enrolled in the individual trials varied from 42 Records identified through Additional records identified
through scientific proceedings (n = 18) (n = 159) (n = 472) (n = 404) (n = 68) (n = 59) (n = 7 full-text articles) (n = 2 abstracts)
Studies included in synthesis
No data on Child C patients Reasons for exclusion: Text articles excluded
Records excluded Records screened
Records after duplicates removed
Text articles assessed Medline searching
(n = 631)
Figure 1 | PRISMAflow diagram showing the study selection process
to 2037, and their median ages were generally<60 years. The majority of patients with cirrhosis were infected by HCV genotype 1, were in Child B class and presented with a mean MELD score of <15. About two-thirds of patients had failed a previous treatment course with peg-interferon and ribavirin.
Information on treatment outcome was available for 228 of the 240 Child C patients evaluated in the 10 tri-als. The SVR12 rates described in the individual studies are shown in Figure 2: the rates varied from low values of 50.0% and 56.3% reported in two studies17, 18 to high values of 94.4% and 96.0% found in two other reports.21, 24 Overall, the weighted mean SVR12 rate was 74.9% (95% CI: 65.6–82.4%) using a random effects model. Several sub-analyses were run to explore the potential impact of the different regimens administered in the selected studies; the individual results are given in Figures S1–S5 and the pooled estimates in Figure 3.
The first sub-analysis considered the effect of the length of treatment: the weighted mean SVR12 rate was 82.3% (95% CI: 0.71–99.0) when treatment lasted for 24 weeks, and 70.9% (95% CI: 62.0–78.5) when treat-ment lasted for 12 weeks (Figure 3 and Figure S1); a trend toward a significant difference was seen (P= 0.085). The inclusion of ribavirin in the treatment schedules did not affect these rates (Figure 3 and Fig-ure S2): the weighted mean value was 76.4% (95% CI: 64.7–85.1) when ribavirin was added to the new anti-virals, and 79.9% (95% CI: 54.9–92.9) when was not (P= 0.758). Next, we analysed the interaction between treatment length and ribavirin administration. When treatment lasted for 24 weeks, the administration of
ribavirin did not affect the SVR12 rates, which were 81.7% (95% CI; 63.1–89.9) and 95.4% (95% CI: 73.5– 93.4%) when ribavirin was and was not administered respectively (Figure S3). When treatment lasted for 12 weeks, the weighted SVR12 rates were 73.6% (95% CI: 62.0–82.7) and 69.2% (95% CI: 47.3–83.7) respec-tively. No previous differences were statistically signi fi-cant (Figure S3).
Sufficient data were available to evaluate the efficacies of three different schedules of direct acting antiviral agents, although no information was available on the efficacy of ombitasvir/paritaprevir and dasabuvir in patients with Child C cirrhosis (Figure S4). The regimen of sofosbuvir plus simeprevir given for 12 weeks was evaluated in four studies:16, 17, 24, 30 in the 31 patients with Child C cirrhosis treated with this schedule, the weighted mean SVR12 rate was 65.4% (95% CI: 46.8– 80.2). In four studies,18, 21, 22, 24 55 patients received sofosbuvir plus daclatasvir, the majority of them for 24 weeks: the corresponding weighted mean SVR12 rate was 76.0% (95% CI: 54.4–89.3%). In three stud-ies,14, 15, 24 sofosbuvir was administered in combination with ledipasvir to 101 patients: a weighted mean SVR12 rate of 83.0% (95% CI: 73.4–89.6) was observed. As this last treatment schedule was given for 12 or 24 weeks, we explored the impact of treatment length on SVR12 rate: weighted mean SVR12 rates were 82.3% (95% CI: 69.0– 90.7) in patients treated for 24 weeks, and 83.5% (95% CI: 69.3–92.0) in those treated for 12 weeks.
The relapse rate after treatment was reported in four studies14–16, 24 and the data are presented in Table 2: only 13 (12.1%) of the 197 patients with Child C
Table 1 | Characteristics of Child classes A–C cirrhotic patients, enrolled in the studies selected for the meta-analysis
Total Mean age (range)
HCV genotype Child classes
Mean MELD (range) MELD> 15 (%) Previous treatment (%) 1 2 3 4 A B C Charlton, 2015 108 59 (53–62) 105 – – 3 – 59 49 (10–25) 41 65 Manns, 2016 107 54 (47–63) 97 – – 10 – 56 51 (10–25) 45 75
Shiffmann, 2015 120 60 (29–79) 120 – – – 81 25 14 N.A. N.A. 61
Foster, 2016 409 54 (28–79) 200 – – 172 71 297 41 12 (7–32) N.A. 60
Modi, 2016 42 58 (32–69) 42 – – – 35 7 (6–25) 9,5 52
Poordad, 2016 60 58 (19–75) 45 5 6 4 12 32 16 13 (8.27) 30 60
Saxena, 2016 156 62 (58–65) 61 – – – 101 49 6 12 (10–14) N.A. 55
Leroy, 2016 93 55 N.A. 85 8 13 N.A. 75
Petersen, 2016 147 56 (28–85) 108 – 39 – – 127 20 N.A. 20 69
Ippolito, 2016 2037 65 (28–88) 1427 350 137 113* 1759 249 29 8 (5–25) 68 49 NA, not assessed.
cirrhosis with available information relapsed after cessa-tion of therapy (12.1%). Data on funccessa-tional outcome after 12 weeks of follow-up were extracted from five studies14, 18, 21, 24 (Table 2): an improvement of ≥2 points at the post-treatment follow-up was documented in 63 of 103 patients (61.1%).
DISCUSSION
The efficacy, safety and long-term outcome of treatment with new direct acting antiviral agents of patients with Child C cirrhosis are unknown, as the low numbers of these patients enrolled in either registrative or post-mar-keting clinical trials do not allow conclusions to be drawn. This lack of information reflects concerns and
fears regarding the treatment of such patients with peg-interferon and ribavirin: although such a therapy has been shown to be feasible,7 the associated severe events and worsening of hepatic decompensation25, 26have dis-couraged physicians from administering interferon-based therapies to patients with Child C. These same concerns and fears also apply to the new interferon-free regimens. While these new regimens have proved safe and effective in patients with Child A and B cirrhosis,8–10 data describing their use in Child C patients are limited. We sought to address this lack of information by conducting a systematic review of the published literature and tried to separate the results for Child C patients from those of the entire cohort of patients with cirrhosis in each trial.
Even rate and 95% CI Even rate 0.867 Charlton, 2015 Manns, 2016 Shiffman, 2015 Foster, 2016 Modi, 2016 Poordad, 2016 Saxena, 2015 Leroy, 2016 Petersen, 2016 Ippolito, 2016 0.783 0.643 0.707 0.714 0.563 0.500 0.944 0.750 0.960 0.765 0.522 0.892 0.997 0.495 0.168 0.324 0.327 0.552 0.376 0.641 0.733 0.939 0.879 0.843 0.826 0.928 0.775 0.832 0.994 0.00 0.50 1.00 0.749 Random 0.656 0.824 Lower limit Upper limit
Figure 2 | Weighted estimates of sustained virological response rates after treatment of patients with Child C cirrhosis with the new direct-acting antivirals in the 10 selected studies.
Overall 24 weeks 12 weeks
P = 0.085 74.9% 100% 90% 80% 70% 60% 50% 40%
Sustained Virological Response
30% 20% 10% 0% 82.3% 70.9% 76.4% 79.9% P = 0.758 RBV+ RBV–
Figure 3 | Summary results of weighted estimates of sustained virological response rates according to the different therapeutic regimens with new direct acting antivirals by treatment duration (24 vs. 12 weeks) or the inclusion or not of ribavirin in the regimens.
We pooled the therapeutic results for 228 Child C patients, the largest collection of such patients evaluated to date. The weighted average SVR12 rate was 74.9% (95% CI: 65.6–82.4%) in the 228 patients treated with the new direct acting antiviral agents in 10 studies. Eight of the surveyed studies had a prospective design, which further validates the observed outcome data. However, we must evaluate this rate carefully because this is an unusual population, as the majority of patients were genotype 1 and previously exposed to peg-interferon plus ribavirin. Nevertheless, this remarkable SVR12 rate indi-cates that this particular setting of HCV-infected patients should not be denied treatment with the new therapeutic regimens.
Although of relevance to physicians caring for these patients, the average SVR rate seen in this investigation is lower than that reported in patients with Child A and B cirrhosis. We tried to explore whether the different schedules adopted in the original investigations might have impacted on the SVR rate in these patients. As indicated in Figure 3, neither duration of treatment (whether 24 or 12 weeks), nor the addiction of ribavirin seemed to make a difference. Numerically higher SVR12 rates were seen when therapy was administered for 24 weeks (82.3% vs. 70.9%), but this difference is likely due to the fact that more patients administered 12 weeks of treatment received therapy with the less effective schedule, that is sofosbuvir in combination with simepre-vir. Indeed, the individual therapeutic regimens
administered to patients resulted in some variation in the SVR12 rates: 65.4% (95% CI: 46.8–80.2) in patients treated with sofosbuvir and simeprevir, 76.0% (95% CI: 54.4–89.3) in those treated with sofosbuvir and daclatas-vir, and 83.0% (95% CI: 73.4–89.6) in those treated with sofosbuvir and ledipasvir. The reasons for the choice of the regimens in the original investigations are unknown, but appeared to be dependent on when the various direct acting antiviral drugs were made available to physicians. On the Italian market, the combination of sofosbuvir and simeprevir was licensed first, followed by sofosbuvir with daclatasvir, and then by sofosbuvir and ledipasvir. Because these regimens were not randomised in the orig-inal investigations, we cannot compare their respective efficacies. However, we note that there was a 17% differ-ence in SVR12 rates between sofosbuvir/simeprevir and sofosbuvir/ledipasvir, so a formal clinical trial comparing these therapeutic schedules is urgently required. In the meanwhile, the data presented here indicate that patients with Child C cirrhosis should be treated with sofosbuvir and ledipasvir, irrespective of ribavirin, for 12 weeks.
A further argument against treating these patients concerns the long-term benefit of therapy, as antiviral treatment in end-stage liver disease might be futile and only marginally affect prognosis. After successful ther-apy, the MELD score will improve in one-third of patients with cirrhosis, deteriorate in one-third and remain stable in one-third.27 Of note, in the present investigation, an improvement of≥2 points in the MELD Table 2 | Characteristics of Child C cirrhotic patients, enrolled in the studies selected for the meta-analysis
Regimen Ribavirin Duration of therapy (weeks) Total no. of patients No. of patients with SVR12 No. of patients who relapsed ≥2 points improvement in MELD score
Charlton, 2015 SOF/LDV Yes 12 22 19 1 8/18
Yes 24 23 20 2 6/20
Manns, 2016 SOF/LDV Yes 12 21 17 3 12/16
Yes 24 25 19 1 13/19
Shiffmann, 2015 SOF/SMV No 12 14 9 5 –
Foster, 2016 SOF/DAC or LDV Yes 12 41 29 – –
Modi, 2016 SOF/SMV No 12 7 5 – –
Poordad, 2016 SOF/DAC Yes 12 16 9 – 7/13
Saxena, 2016 SOF/SMV 12 6 33 – –
Leroy, 2016 SOF/DAC No 24 8 8 – 3/4
Petersen, 2016 SOF/DAC 24 20 15 – –
Ippolito, 2016 SOF/DAC Yes 24 6 5 1 3/6
No 24 5 5 – 4/5
SOF/LDV Yes 24 3 3 – 3/3
No 24 7 7 – 3/7
SOF/SMV Yes 12 2 2 – 1/2
score was seen in 61.1% of the Child C patients during follow-up. Unfortunately, the MELD score was only available for 103 of the 228 treated Child C patients, but the percentage of patients with an improved MELD score was remarkable. The difference seen between our data and previous studies on post-treatment benefit in patients with decompensated cirrhosis22, 23 may be par-tially be due to the characteristics of the investigated patients: our survey was restricted to Child C patients, while in previous studies the majority of cases had Child B cirrhosis. About 50% of our patients with cirrhosis presented with a MELD score >15 at baseline, and the higher the MELD scores at baseline the more likely an improvement is seen at the post-treatment evaluation.
Our investigation may have some limitations. Although the present collection represents the largest series to date of patients with Child C cirrhosis, in several sub-analyses the size of the investigated cohort limited our ability to draw conclusions. For instance, we cannot compare the different regimens because the reasons for choosing the regimen are not known: about three quarters of the patients received a combination of sofosbuvir with ledi-pasvir, and only a minority the other three currently avail-able regimens. A second issue is that the patients included in the three largest studies12, 13, 19had an upper age limit of 63 years, so we do not have sufficient evidence to rec-ommend treatment for older subjects. We tried to retrieve information on safety of the new antivirals administered to Child C patients, being aware of reports on the risk of hepatic decompensation following this therapy.28, 29 In 2015, the FDA issued a warning against the administration of the new antivirals in patients with Child B and C cir-rhosis, based on 26 cases of worsening liver failure.30 Unfortunately, data on the safety of antiviral treatments and mortality during therapy in Child C patients in the original studies could not been analysed, as this informa-tion could not be extracted from the informainforma-tion from entire populations. Nutt et al. have reported that the over-all incidence of hepatic decompensation in patients with cirrhosis treated with the newer direct antivirals was higher in those treated with sofosbuvir/simeprevir than in those treated with sofosbuvir/ledispavir.31 We acknowl-edge this lack of data as a major limitation of the present investigation. Finally, the majority of treated patients in this analysis were infected with HCV genotype 1 and so the results refer to this subset of patients but may not apply to HCV genotypes 3 and 4. Despite these concerns,
the overall SVR12 rates in this study are reassuring for patients with Child C cirrhosis.
In conclusion, the outcomes of the studies analysed in this review provide evidence for the effectiveness of the new interferon-free regimens for patients with Child C cirrhosis: their efficacy together with the remarkable improvement in post-treatment MELD scores indicate this subgroup of patients with severely impaired liver function should be treated. There is an urgent need to conduct a formal observational trial to evaluate the effi-cacy, safety and post-treatment outcome of the new pro-tease inhibitors in patients with Child C cirrhosis.
SUPPORTING INFORMATION
Additional Supporting Information may be found in the online version of this article:
Figure S1. The impact of treatment duration (24 or 12 weeks) on sustained virological response to direct act-ing antivirals in patients with Child C cirrhosis.
Figure S2. Sustained virological response to the administration of the new antivirals in patients with Child C cirrhosis when ribavirin was or not included in the therapeutic regimens
Figure S3. Sustained virological response rates to the administration of direct acting antiviral agents in patients with Child C cirrhosis by treatment duration (24 or 12 weeks) and ribavirin administration (yes or no)
Figure S4. Sustained virological response rates by treatment regimens in patients with Child C cirrhosis.
Figure S5. Effect of treatment duration (24 or 12 weeks) in patients with Child C cirrhosis who received therapy with sofosbuvir and ledipasvir.
AUTHORSHIP
Guarantor of the article: A. Andriulli
Author contributions: Antonio Massimo Ippolito declares that there are no known conflicts of interest associated with this publication. The statistic analysis was drawn by MR Valvano. The Medline search was conducted by Guarino Maria, Antonio Massimo Ippolito and Filomena Morisco. Marta Librandi, Nicola Andriulli, Monica Greco, Annabianca Amoruso, Angelo Iacobellis, Grazia Niro, and Nicola Caporaso have contributed to the scientific discussion of the data. Angelo Andriulli wrote and developed the paper. Antonio Massimo Ippolito declares that there are no known conflicts of interest associated with this publication.
All authors approved thefinal version of the manuscript.
ACKNOWLEDGEMENTS
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